Hydroxylamine and nitroso metabolites have been implicated in the pathogenesis of adverse reactions to sulfamethoxazole (SMX) and other arylamine drugs. Hydroxylamines spontaneously oxidize to reactive nitroso metabolites, which, in the case of SMX, can trigger delayed-type hypersensitivity reactions. These hypersensitivity reactions interfere with the effective use of SMX, which is the drug of choice for the prevention of opportunistic infections in immunocompromised patients. Studies of metabolic risk factors for SMX hypersensitivity have largely yielded negative results; however, these studies have not considered the reductive metabolism of hydroxylamine and nitroso metabolites. We have recently shown that hydroxylamines are detoxified by the flavoprotein NADH cytochrome b5 reductase (b5R) and the hemeprotein cytochrome b5 (cyt b5), through a novel, direct pathway of xenobiotic reduction. We have also shown that ascorbate, in addition to thiols, provides a major pathway of nitroso reduction. Our overall hypothesis is that impaired hydroxylamine or nitroso reduction predisposes patients to adverse reactions to arylamine compounds, such as hypersensitivity to SMX. We will address this hypothesis by first characterizing variability in hydroxylamine reduction and its relationship to genetic polymorphisms in b5R or cyt b5 in humans. We will next determine whether alterations in hydroxylamine or nitroso reduction influence the immunogenic response to SMX metabolites, using ascorbate, thiol, or flavin restriction in a guinea pig model. Finally, we will determine whether impaired hydroxylamine or nitroso reduction is a risk factor for SMX hypersensitivity, in a prospective study of immunocompromised patients with lymphoid malignancies. These studies will advance our understanding of the mechanisms underlying SMX hypersensitivity, and will characterize individual variability in a novel direct pathway of xenobiotic reduction, with clinical implications for responses to many compounds, including amidoxime pro-drugs and arylamine carcinogens, in addition to SMX. Relevance: These studies will help us to better understand individual risk factors that lead to """"""""sulfa drug"""""""" allergies in people, by learning about differences in the ways that sulfa drugs are metabolized by different people. The ultimate goal of these studies is to find better ways to prevent these adverse reactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061753-08
Application #
7404561
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2000-07-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
8
Fiscal Year
2008
Total Cost
$271,200
Indirect Cost
Name
University of Wisconsin Madison
Department
Other Basic Sciences
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Blanke, Kristina L; Sacco, James C; Millikan, Robert C et al. (2014) Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women. Cancer Causes Control 25:1513-21
Sacco, James C; Abouraya, Mahmoud; Motsinger-Reif, Alison et al. (2012) Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity. Pharmacogenet Genomics 22:733-40
Abouraya, Mahmoud; Sacco, James C; Hayes, Kristie et al. (2012) Dapsone-associated methemoglobinemia in a patient with slow NAT2*5B haplotype and impaired cytochrome b5 reductase activity. J Clin Pharmacol 52:272-8
Funk-Keenan, J; Sacco, J; Wong, Y Y Amos et al. (2012) Evaluation of polymorphisms in the sulfonamide detoxification genes CYB5A and CYB5R3 in dogs with sulfonamide hypersensitivity. J Vet Intern Med 26:1126-33
Abouraya, Mahmoud; Sacco, James C; Kahl, Brad S et al. (2011) Evaluation of sulfonamide detoxification pathways in haematologic malignancy patients prior to intermittent trimethoprim-sulfamethoxazole prophylaxis. Br J Clin Pharmacol 71:566-74
Rhoads, Keelia; Sacco, James C; Drescher, Nicholas et al. (2011) Individual variability in the detoxification of carcinogenic arylhydroxylamines in human breast. Toxicol Sci 121:245-56
Sacco, James C; Trepanier, Lauren A (2010) Cytochrome b5 and NADH cytochrome b5 reductase: genotype-phenotype correlations for hydroxylamine reduction. Pharmacogenet Genomics 20:26-37
Bhusari, Sachin; Abouraya, Mahmoud; Padilla, Marcia L et al. (2010) Combined ascorbate and glutathione deficiency leads to decreased cytochrome b5 expression and impaired reduction of sulfamethoxazole hydroxylamine. Arch Toxicol 84:597-607
Gan, Lu; von Moltke, Lisa L; Trepanier, Lauren A et al. (2009) Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes. Drug Metab Dispos 37:90-6
Lavergne, S N; Drescher, N J; Trepanier, L A (2008) Anti-myeloperoxidase and anti-cathepsin G antibodies in sulphonamide hypersensitivity. Clin Exp Allergy 38:199-207

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